Reduced influenza viral neutralizing activity of natural human trimers of surfactant protein D

BACKGROUND. Surfactant protein D (SP-D) plays important roles in innate host defense against influenza A virus (IAV) infection. Common human polymorphisms of SP-D have been found in many human populations and associated with increased risk of certain infections. We recently reported that the Thr/Thr 11 form of SP-D is associated with low serum levels and assembles predominantly as trimers as opposed to the more common multimeric forms of SP-D. METHODS. Preliminary experiments were done to establish the effects of different monoclonal antibodies against SP-D on ability of SP-D to bind to or neutralize the virus. We then purified natural human trimeric and multimeric forms of SP-D from amniotic fluid and tested ability of these preparations to bind to IAV, to inhibit infectivity and hemagglutination activity of IAV in vitro. RESULTS. In initial experiments mAbs directed against different areas on the CRD of SP-D were found to have differing effects on antiviral activity. Using an mAb that did not interfere with antiviral activity of SP-D, we confirm that natural SP-D trimers had reduced ability to bind to IAV. In addition, the trimers had reduced ability to neutralize IAV as compared to natural human SP-D multimers as well as reduced hemagglutination inhibiting activity against several strains of IAV. Natural SP-D trimers also had different interactions with human neutrophil peptide defensins (HNPs) in viral neutralization assays as compared to multimeric SP-D. CONCLUSION. These studies indicate that a common human polymorphic form of SP-D may modulate host defense against IAV and give impetus to clinical studies correlating this genotype with risk for IAV infection in susceptible groups. We also show that mAbs directed against different areas on the carbohydrate recognition domain of SP-D can be useful for dissecting out different functional properties of the protein

QALYs, DALYs, and HALYs: A unifying framework for the evaluation of population health

We provide a unifying framework for the evaluation of population health. We formalize several axioms for social preferences over distributions of health. We show that a specific combination of those axioms characterizes a large class of population health evaluation functions combining concerns for quality of life, quantity of life and health shortfalls. We refer to the class as (unweighted) aggregations of health-adjusted life years (HALYs). Two focal (and somewhat polar) members of this family are the (unweighted) aggregations of quality-adjusted life years (QALYs), and of disability-adjusted life years (DALYs). We also provide new characterization results for these focal members that enable us to scrutinize their normative foundations and shed new light on their similarities and differences.Universidad Pablo de Olavide. Departamento de Economía, Métodos Cuantitativos e Historia Económic

1-(3-Bromo­prop­yl)-4-(2-pyrid­yl)-1H-1,2,3-triazole

In the structure of the title compound, C10H11BrN4, the plane of the substituted 1,2,3-triazole ring is tilted by 14.84 (10)° with respect to the mean plane of the pyridine ring. The pyridine and closest triazole N atoms adopt an anti arrangement which removes any lone pair–lone pair repulsions between the N atoms. This conformation is further stabilized by weak intermolecular C—H⋯N inter­actions. There are two mol­ecules in the unit cell, which form a centrosymmetric head-to-tail dimer. The dimers are stabilized through π–π inter­actions [centroid–centroid distance = 3.733 (4) Å and mean inter­planar distance = 3.806 (12) Å] between the substituted 1,2,3-triazole ring and the pyridine rings in adjacent mol­ecules. Each dimer inter­acts with two neighbouring dimers above and below, forming a slipped stack of dimers through the crystal. The 3-bromo­propyl chain sits over the pyridine ring of a neighbouring mol­ecule and the triazole rings of nearby mol­ecules are adjacent

Heterogeneous Catalysis through Microcontact Printing

Here, we investigate four different chemical pathways (Scheme 1a–d) relevant to the Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction.[13] Three of those pathways lead to surfaces functionalized with organic molecules.[5, 11, 14] At the outset, our practical goal was to identify surface-functionalization protocols that are capable of attaining 1) spatial selectivity, 2) high surface coverage, and 3) rapid reaction kinetics. Our ultimate goal is to achieve a fundamental understanding of how different reaction pathways influence the chemical outcome as it applies to the organic functionalization of surfaces

Sequence-selective DNA recognition and enhanced cellular up-take by peptide–steroid conjugates

Several GCN4 bZIP TF models have previously been designed and synthesized. However, the synthetic routes towards these constructs are typically tedious and difficult. We here describe the substitution of the Leucine zipper domain of the protein by a deoxycholic acid derivative appending the two GCN4 binding region peptides through an optimized double azide–alkyne cycloaddition click reaction. In addition to achieving sequence specific dsDNA binding, we have investigated the potential of these compounds to enter cells. Confocal microscopy and flow cytometry show the beneficial influence of the steroid on cell uptake. This unique synthetic model of the bZIP TF thus combines sequence specific dsDNA binding properties with enhanced cell-uptake. Given the unique properties of deoxycholic acid and the convergent nature of the synthesis, we believe this work represents a key achievement in the field of TF mimicry

Supramolecular Assemblies Constructed by Cucurbituril-Catalyzed Click Reaction

Cataloged from PDF version of article.Cucurbituril homologues are multi-functional macrocycles that can find applications in many areas and have numerous interesting features setting them apart from the other macrocycles. Among them, the ability of one of the cucurbituril homologues, cucurbit[6]uril (CB6), to catalyze 1,3-dipolar cycloaddition in a regiospecific fashion is truly exceptional. Using this feature, small molecules can be clicked together to form complex structures in a very efficient way. Accordingly, in this article we review recent research involving the use of CB6-catalyzed 1,3-dipolar cycloaddition or the click reaction of CB6 in the construction of supramolecular assemblies including rotaxanes, pseudorotaxanes, polyrotaxanes, polypseudorotaxanes, molecular switches, machines, and nanovalves

Site-specific terminal and internal labeling of RNA by poly(A) polymerase tailing and copper-catalyzed or copper-free strain-promoted click chemistry

The modification of RNA with fluorophores, affinity tags and reactive moieties is of enormous utility for studying RNA localization, structure and dynamics as well as diverse biological phenomena involving RNA as an interacting partner. Here we report a labeling approach in which the RNA of interest—of either synthetic or biological origin—is modified at its 3′-end by a poly(A) polymerase with an azido-derivatized nucleotide. The azide is later on conjugated via copper-catalyzed or strain-promoted azide–alkyne click reaction. Under optimized conditions, a single modified nucleotide of choice (A, C, G, U) containing an azide at the 2′-position can be incorporated site-specifically. We have identified ligases that tolerate the presence of a 2′-azido group at the ligation site. This azide is subsequently reacted with a fluorophore alkyne. With this stepwise approach, we are able to achieve site-specific, internal backbone-labeling of de novo synthesized RNA molecules